1. Ureteral or urethral obstruction by strictures, stones, external compression, pelvic tumors, and so forth
2. Obstructing tumors of bladder; congenital defects in bladder or urethra
3. Prostatic obstruction (tumor or benign hypertrophy; a very common cause in elderly men)

Prerenal azotemia etiologies can be divided into two main categories: (1) decreased blood volume or renal circulation and (2) increased protein intake or endogenous protein catabolism.

In azotemia due to excessive protein, some of the more common clinical situations are high-protein tube feedings or gastrointestinal (GI) tract hemorrhage (where protein is absorbed from the GI tract); low-calorie diet (as in patients receiving intravenous [IV] fluids, leading to endogenous protein catabolism); and adrenocortical steroid therapy (since these substances have a catabolic action).

In decreased renal blood flow, etiologies include blood volume deficit, cardiac failure to pump sufficient blood, or toxic effects on blood vessels. It should be pointed out that decreased renal blood flow may produce prerenal azotemia without structural renal damage, but it may also produce severe acute renal damage (acute renal failure, also called acute tubular necrosis).

Primary renal disease may produce azotemia due to primarily glomerular or tubular destructive conditions or to diffuse parenchymal destruction. Rarely is there glomerular damage to the point of severe azotemia (5%-10% of AGN cases) without some effect on the tubules, and vice versa. Therefore, the BUN level must be correlated with other clinical findings before its significance can be interpreted. There is nothing etiologically distinctive about the terminal manifestations of chronic kidney disease, and it is most important to rule out treatable diseases that may simulate the uremic laboratory or clinical picture. Anuria (urine output <100 ml/24 hours) always suggests urinary obstruction.

Terminal azotemia, sometimes to uremic levels, occurs in the last hours or days of a significant number of seriously ill patients with a variety of diseases, including cancer. Often no clinical or pathologic cause is found, even microscopically. Urine specific gravity may be relatively good.

Serum creatinine

Serum creatinine is derived from muscle metabolism, as described earlier. Serum creatinine levels are dependent on body muscle mass; the greater the muscle mass, the higher the creatinine value, both in serum and urine. Creatinine values increase after meals, with the greatest increases (20%-50%) after meat ingestion. There is said to be a diurnal variation, with the lowest values about 7 A.M. and the peak about 7 P.M.; the late-afternoon values are reported to be about 20%-40% higher than in the morning. Some of the variation may be related to meals. Reference values for females are about 90% of those for males.

Normally, the BUN/serum creatinine ratio is approximately 10:1. Under standard conditions a 50% decrease in the GFR produces an approximate doubling of the BUN level or serum creatinine level, and the reverse occurs when the GFR is increased. However, these relationships can be altered by many factors, including those that increase or decrease either BUN or serum creatinine level without affecting the other. Conditions that decrease creatinine production (age-related decrease, muscle wasting, low-meat diet) may partially mask serum creatinine elevation due to renal disease. The serum creatinine level has much the same significance as the BUN level but tends to rise later. Significant creatinine elevations thus suggest chronicity without being diagnostic of it.

Laboratory methodology. Creatinine is most often assayed by a chemical method (Jaffe reaction) that includes about 20% noncreatinine substances. Elevated ketones and certain cephalosporin antibiotics (cephalothin, cefoxitin, cefazolin, cephalexin, cefaclor, cephradine) may produce false elevation of creatinine assays in serum or urine using the Jaffe reaction. Several enzymatic methods for creatinine assay are now available that are specific for creatinine and produce creatinine values that are lower and creatinine clearance results that are higher than those derived from the Jaffe reaction. Certain medications (cimetidine, probenecid, trimethoprim) interfere with tubular secretion of creatinine, increasing serum creatinine and decreasing creatinine clearance.

Summary of glomerular function studies

Clearance as a measurement of overall renal function impairment yields roughly the same information as that obtained from the phenolsulfonphthalein (PSP) test and has mostly replaced it in practice. Clearance tests are reliable in detecting mild to moderate diffuse renal disease, but they depend on completely collected specimens and accurate recording of the time the specimens were collected and presuppose adequate renal blood flow. If a patient is incontinent of urine, one must use either a short period of collection or a catheter or else some other test. Of course, if a Foley catheter is already in place, there is no problem. A clearance value between 60% and 80% of normal is usually taken to represent mild diffuse renal function impairment. Values between 40% and 60% of normal represent moderate decrease, and values between 20% and 40% of normal are considered severe renal function impairment, since about one half of the patients in this group also have an elevated BUN level. Most (but not all) of the causes of an increased BUN level also result in a considerable decrease in creatinine clearance. When the serum creatinine level is elevated in addition to the BUN level, a creatinine clearance rate less than 40 ml/minute (and usually < 25 ml/minute) can be predicted with reasonable assurance (Fig. 13-1). Therefore, as long as the BUN level is significantly elevated (except in unusual cases when BUN elevation is due to increased protein load), and especially if azotemia is accompanied by an elevated serum creatinine level, clearance tests usually do not provide additional information.

Correlation of renal function test results. Dotted box represents clearance values found when blood urea nitrogen (BUN) or serum creatinine level begins to rise.

Fig. 13-1 Correlation of renal function test results. Dotted box represents clearance values found when blood urea nitrogen (BUN) or serum creatinine level begins to rise.

The question sometimes arises whether both the BUN and the serum creatinine should be assayed to screen for decreased renal function. In 130 consecutive patients in our hospital whose admission BUN or creatinine were elevated, 47% had elevated levels of both, 38% had elevated BUN levels only, and 15% had an elevated creatinine level only.

In the classic case of chronic diffuse bilateral renal disease, the first demonstrable test abnormality is a decrease in urine-concentrating ability in the concentration test. As the disease progresses, the creatinine clearance becomes reduced. Then the specific gravity becomes fixed, and there is a considerable decrease in creatinine clearance. Finally, clearance becomes markedly decreased, and the BUN level starts to rise, followed shortly by the serum creatinine level.

The question sometimes is raised as to the degree of BUN increase that is possible in short periods of time. In one study, daily increase after onset of acute renal failure ranged from 10 to 50 mg/100 ml (3.5 to 18 mmol/L) during the first week, with the average daily increase being 25 mg/100 ml (9 mmol/L). After the first week, the amount of increase tended to be less.

1.
Ureteral or urethral obstruction by strictures, stones, external compression, pelvic tumors, and so forth

2.
Obstructing tumors of bladder; congenital defects in bladder or urethra

3.
Prostatic obstruction (tumor or benign hypertrophy; a very common cause in elderly men)
Prerenal azotemia etiologies can be divided into two main categories: (1) decreased blood volume or renal circulation and (2) increased protein intake or endogenous protein catabolism.
In azotemia due to excessive protein, some of the more common clinical situations are high-protein tube feedings or gastrointestinal (GI) tract hemorrhage (where protein is absorbed from the GI tract); low-calorie diet (as in patients receiving intravenous [IV] fluids, leading to endogenous protein catabolism); and adrenocortical steroid therapy (since these substances have a catabolic action).
In decreased renal blood flow, etiologies include blood volume deficit, cardiac failure to pump sufficient blood, or toxic effects on blood vessels. It should be pointed out that decreased renal blood flow may produce prerenal azotemia without structural renal damage, but it may also produce severe acute renal damage (acute renal failure, also called acute tubular necrosis).
Primary renal disease may produce azotemia due to primarily glomerular or tubular destructive conditions or to diffuse parenchymal destruction. Rarely is there glomerular damage to the point of severe azotemia (5%-10% of AGN cases) without some effect on the tubules, and vice versa. Therefore, the BUN level must be correlated with other clinical findings before its significance can be interpreted. There is nothing etiologically distinctive about the terminal manifestations of chronic kidney disease, and it is most important to rule out treatable diseases that may simulate the uremic laboratory or clinical picture. Anuria (urine output <100 ml/24 hours) always suggests urinary obstruction.
Terminal azotemia, sometimes to uremic levels, occurs in the last hours or days of a significant number of seriously ill patients with a variety of diseases, including cancer. Often no clinical or pathologic cause is found, even microscopically. Urine specific gravity may be relatively good.
Serum creatinine
Serum creatinine is derived from muscle metabolism, as described earlier. Serum creatinine levels are dependent on body muscle mass; the greater the muscle mass, the higher the creatinine value, both in serum and urine. Creatinine values increase after meals, with the greatest increases (20%-50%) after meat ingestion. There is said to be a diurnal variation, with the lowest values about 7 A.M. and the peak about 7 P.M.; the late-afternoon values are reported to be about 20%-40% higher than in the morning. Some of the variation may be related to meals. Reference values for females are about 90% of those for males.
Normally, the BUN/serum creatinine ratio is approximately 10:1. Under standard conditions a 50% decrease in the GFR produces an approximate doubling of the BUN level or serum creatinine level, and the reverse occurs when the GFR is increased. However, these relationships can be altered by many factors, including those that increase or decrease either BUN or serum creatinine level without affecting the other. Conditions that decrease creatinine production (age-related decrease, muscle wasting, low-meat diet) may partially mask serum creatinine elevation due to renal disease. The serum creatinine level has much the same significance as the BUN level but tends to rise later. Significant creatinine elevations thus suggest chronicity without being diagnostic of it.
Laboratory methodology. Creatinine is most often assayed by a chemical method (Jaffe reaction) that includes about 20% noncreatinine substances. Elevated ketones and certain cephalosporin antibiotics (cephalothin, cefoxitin, cefazolin, cephalexin, cefaclor, cephradine) may produce false elevation of creatinine assays in serum or urine using the Jaffe reaction. Several enzymatic methods for creatinine assay are now available that are specific for creatinine and produce creatinine values that are lower and creatinine clearance results that are higher than those derived from the Jaffe reaction. Certain medications (cimetidine, probenecid, trimethoprim) interfere with tubular secretion of creatinine, increasing serum creatinine and decreasing creatinine clearance.
Summary of glomerular function studies
Clearance as a measurement of overall renal function impairment yields roughly the same information as that obtained from the phenolsulfonphthalein (PSP) test and has mostly replaced it in practice. Clearance tests are reliable in detecting mild to moderate diffuse renal disease, but they depend on completely collected specimens and accurate recording of the time the specimens were collected and presuppose adequate renal blood flow. If a patient is incontinent of urine, one must use either a short period of collection or a catheter or else some other test. Of course, if a Foley catheter is already in place, there is no problem. A clearance value between 60% and 80% of normal is usually taken to represent mild diffuse renal function impairment. Values between 40% and 60% of normal represent moderate decrease, and values between 20% and 40% of normal are considered severe renal function impairment, since about one half of the patients in this group also have an elevated BUN level. Most (but not all) of the causes of an increased BUN level also result in a considerable decrease in creatinine clearance. When the serum creatinine level is elevated in addition to the BUN level, a creatinine clearance rate less than 40 ml/minute (and usually < 25 ml/minute) can be predicted with reasonable assurance (Fig. 13-1). Therefore, as long as the BUN level is significantly elevated (except in unusual cases when BUN elevation is due to increased protein load), and especially if azotemia is accompanied by an elevated serum creatinine level, clearance tests usually do not provide additional information.

Fig. 13-1 Correlation of renal function test results. Dotted box represents clearance values found when blood urea nitrogen (BUN) or serum creatinine level begins to rise.

The question sometimes arises whether both the BUN and the serum creatinine should be assayed to screen for decreased renal function. In 130 consecutive patients in our hospital whose admission BUN or creatinine were elevated, 47% had elevated levels of both, 38% had elevated BUN levels only, and 15% had an elevated creatinine level only.
In the classic case of chronic diffuse bilateral renal disease, the first demonstrable test abnormality is a decrease in urine-concentrating ability in the concentration test. As the disease progresses, the creatinine clearance becomes reduced. Then the specific gravity becomes fixed, and there is a considerable decrease in creatinine clearance. Finally, clearance becomes markedly decreased, and the BUN level starts to rise, followed shortly by the serum creatinine level.
The question sometimes is raised as to the degree of BUN increase that is possible in short periods of time. In one study, daily increase after onset of acute renal failure ranged from 10 to 50 mg/100 ml (3.5 to 18 mmol/L) during the first week, with the average daily increase being 25 mg/100 ml (9 mmol/L). After the first week, the amount of increase tended to be less.